Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC1SC=C(/C(=N/OC(C(OC(C2C=CC=CC=2)C2C=CC=CC=2)=O)C2C=CC(OC(=O)C)=C(OC(=O)C)C=2)/C(N[C@@H:30]2[C:57](=[O:58])[N:32]3[C:33]([C:45]([O:47]CC4C=CC(OC)=CC=4)=[O:46])=[C:34]([CH:37]=[CH:38][C:39]4[S:43][CH:42]=[N:41][C:40]=4[CH3:44])[CH2:35][S:36][C@H:31]23)=O)N=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1.[F:100][C:101]([F:106])([F:105])[C:102]([OH:104])=[O:103]>C(Cl)Cl>[F:100][C:101]([F:106])([F:105])[C:102]([OH:104])=[O:103].[CH3:44][C:40]1[N:41]=[CH:42][S:43][C:39]=1[CH:38]=[CH:37][C:34]1[CH2:35][S:36][C@@H:31]2[CH2:30][C:57](=[O:58])[N:32]2[C:33]=1[C:45]([OH:47])=[O:46]
Reactant: COc1ccc(COC(=O)C2=C(C=Cc3scnc3C)CS[C@@H]3[C@H](NC(=O)/C(=N\OC(C(=O)OC(c4ccccc4)c4ccccc4)c4ccc(OC(C)=O)c(OC(C)=O)c4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ncsc1C=CC1=C(C(=O)O)N2C(=O)C[C@H]2SC1
Reaction time: 1.5 h

Procedure:
709 mg (0.558 mmol) of 4-methoxybenzyl 7β-[(Z)-2-(2-tritylamino-4-thiazolyl)-2-[[(R S)-(diphenylmethoxy carbonyl)(3,4-diacetoxyphenyl)methoxyl]imino]acetamido]-3-[2-(4-methyl-5-thiazolyl)vinyl]-3-cephem-4-carboylate was dissolved in 7 ml of methylene chloride and 2.8 ml of anisole and then 11.2 ml of trifluoroacetic acid was added under and then 11.2 ml of trifluoroacetic acid was added under ice-cooling and the reaction was performed for 90 min. Methylene chloride and trifluoroacetic acid were evaporated under the reduced pressure and the resultant residue was powdered with ethyl ether-hexane(1:1). The powder collected by filtration was further dissolved in 40 ml of trifluoroacetic acid under ice-cooling and then 10 ml of water was added and the reaction was performed for 2.5 hrs. at the room temperature. Trifluoroacetic acid and water were evaporated under the reduced pressure and to the resultant residue was added ethyl ether to powder and collected by filtration to give 298 mg of 7β -[(Z)-2-(2-amino-4-thiazolyl)-2[[(R S)-carboxy)(3,4-diacetoxyphenyl)methoxy]imino]acetamido]-3-[2-(4-methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid trifluoroacetate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][C:12]([CH2:19][OH:20])([C:14]([O:16]CC)=[O:15])[O:11][N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][C:12]([CH2:19][OH:20])([C:14]([OH:16])=[O:15])[O:11][N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOC(=O)C1(CO)CC(c2cc(Cl)cc(Cl)c2)=NO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1(CO)CC(c2cc(Cl)cc(Cl)c2)=NO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2.80 g (8.80 mmol) of ethyl 3-(3,5-dichlorophenyl)-5-(hydroxymethyl)-4,5-dihydro-1,2-oxazole-5-carboxylate were dissolved in 100 ml of methanol, and a solution of mg (11.4 mmol) of NaOH in 20 ml of water was added. After 18 h of stirring at RT, the solvents were removed under reduced pressure, water and methylene chloride were added and the organic phase was separated off. On acidification of the aqueous phase, the product separated off as a white precipitate, which was filtered off and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][N:7]1[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][C:9]=2[Cl:11])[CH:5]=[CH:6]1
Reactant: Clc1cc(Cl)c2[nH]ccc2c1
Reactant: BrCCCCBr
Product: Clc1cc(Cl)c2c(ccn2CCCCBr)c1

Procedure:
The procedure is as for Example 39 using as substrate 5,7-dichloro-1H-indole and 1,4-dibromobutane.
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH:8]=O)#[N:2].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH2:8][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14])#[N:2]
Reactant: C1CCNC1
Reactant: COc1ccc(C=O)cc1OCC#N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COc1ccc(CN2CCCC2)cc1OCC#N
Temperature: 0 °C
Yield: 63.5 %

Procedure:
To a solution of 3-cyanomethoxy-4-methoxybenzaldehyde (10.0 g) in 1,2-dichloroethane (400 ml) was added pyrrolidine (6.6 ml), with stirring, followed by sodium triacetoxyborohydride (22 g). The reaction mixture was stirred at ambient temperature for 1 hr and poured into ice/water 10% sodium hydroxide solution. The mixture was extracted with ethyl acetate, washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was dissolved in dichloromethane and high performance liquid chromatographed, eluting with dichloromethane, 1%, 2% and 5% methanol/dichloromethane. The appropriate fractions were collected and concentrated to give 8.7 g (63.5%) of product as an oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.C([Li])CCC.[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[C:27]1[CH:40]=[CH:39][C:38]2[C:37](=O)[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30][C:29]=2[CH:28]=1.Cl>C1COCC1.CCCCCC>[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[C:27]1[CH:40]=[CH:39][C:38]2[C:29](=[CH:30][C:31]3[C:36]([C:37]=2[C:2]2[CH:11]=[CH:10][C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH:3]=2)=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:28]=1
Reactant: O=C1c2ccccc2Cc2cc(-c3ccc4ccccc4c3)ccc21
Reactant: Brc1ccc2ccccc2c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: c1ccc2cc(-c3ccc4c(-c5ccc6ccccc6c5)c5ccccc5cc4c3)ccc2c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 31.9 %

Procedure:
Under an argon atmosphere, a solution of 4.81 g of 2-bromonaphthalene in 30 mL of THF was cooled to −78° C. Subsequently, 25 mL of a 1.6-M solution of n-butyllithium in hexane were dropped to the solution, and then the mixture was stirred at −78° C. for 1 hour. A solution of 6.76 g of 2-(2-naphthyl)-10-anthrone in 20 mL of THF was added to the mixture, and then the resultant reaction solution was stirred for 5 hours at 50° C. under heat. After the reaction solution had been cooled to room temperature, 100 mL of 10% hydrochloric acid were added to the solution. After the water layer had been removed, the organic layer was washed with water and a saturated salt solution. Then, the organic layer was dried with magnesium sulfate. The solvent was removed by distillation under reduced pressure, and then the residue was purified by silica gel column chromatography. Thus, 2.90 g of 2,10-di(2-naphthyl)anthracene were obtained (in 32% yield).
Reaction SMILES: [N+:1]([C:4]1[C:13]2[O:12][CH2:11][CH2:10][O:9][C:8]=2[CH:7]=[CH:6][C:5]=1[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])([O-:3])=[O:2].[H-].[Na+].S(OC)(O[CH3:28])(=O)=O.O>CN(C=O)C>[CH3:28][N:14]([C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:10][CH2:11][O:12][C:13]=2[C:4]=1[N+:1]([O-:3])=[O:2])[C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1[N+](=O)[O-])OCCO2
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1ccc2c(c1[N+](=O)[O-])OCCO2
Temperature: 0 °C
Yield: 90.9 %

Procedure:
A mixture of tert-butyl 5-nitro-2,3-dihydrobenzo[b][1,4]dioxin-6-ylcarbamate (2.3 g, 7.8 mmol) in DMF (25 mL) was stirred at 0° C. Sodium hydride (373 mg, 9.3 mmol) was added slowly. Dimethyl sulfate (1.017 g, 9.3 mmol) was added dropwise and the mixture was stirred at 0° C. for 0.5 h. To the reaction mixture was slowly added water (40 mL). The mixture was extracted with toluene (40 mL), the organic phase was washed with water (40 mL) and dried, and the solvent removed. The product was purified by silica gel column (5% v/v EtOAc in PE) to give tert-butyl methyl(5-nitro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)carbamate (2.2 g, 92% yield). ESI MS: m/z 311 [M+H]+,
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([Cl:18])[C:3]=1[CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].[H-].[Na+].Br[CH2:22][CH2:23][C:24]([F:27])([F:26])[F:25]>CN(C)C=O>[Cl:1][C:2]1[CH:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:11]=[C:10]([Cl:18])[C:3]=1[CH2:4][C:5]([CH2:22][CH2:23][C:24]([F:27])([F:26])[F:25])([C:6]#[N:7])[C:8]#[N:9]
Reactant: FC(F)(F)CCBr
Reactant: N#CC(C#N)Cc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 52.7 %

Procedure:
Using 0.30 g of (2,6-dichloro-4-(trifluoromethyl)benzyl)malononitrile, 5 ml of N,N-dimethylformamide, 0.05 g of sodium hydride (60% in oil), and 0.20 g of 1-bromo-3,3,3-trifluoropropane, and according to the process described in the Production Example 1, there was obtained 0.21 g of 2-(2,6-dichloro-4-(trifluoromethyl)benzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (7)).
Reaction SMILES: [H-].[Na+].[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([OH:37])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][N:30]=1)=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:39]1[N:44]=[CH:43][N:42]=[C:41]2[N:45]([C:48]3[C:49]([CH3:56])=[C:50]([CH:53]=[CH:54][CH:55]=3)[C:51]#[N:52])[N:46]=[CH:47][C:40]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O.CCOC(C)=O>[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([O:37][C:39]1[N:44]=[CH:43][N:42]=[C:41]2[N:45]([C:48]3[CH:55]=[CH:54][CH:53]=[C:50]([C:51]#[N:52])[C:49]=3[CH3:56])[N:46]=[CH:47][C:40]=12)[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][N:30]=1)=[O:27])([C:16]([CH3:17])([CH3:18])[CH3:19])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cc1c(C#N)cccc1-n1ncc2c(Cl)ncnc21
Reactant: CC(C)(C)[Si](OCCOC[C@H](O)C(=O)Nc1ccc(C#N)cn1)(c1ccccc1)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(C#N)cccc1-n1ncc2c(O[C@@H](COCCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C(=O)Nc3ccc(C#N)cn3)ncnc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 35.1 %

Procedure:
Sodium hydride (60% in oil) (87 mg, 2.17 mmol) was added to (S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-N-(5-cyanopyridin-2-yl)-2-hydroxypropanamide (Intermediate AU1) (484 mg, 0.99 mmol) in anhydrous THF (25 ml) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 3-(4-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-methylbenzonitrile (Intermediate AT2) (267 mg, 0.99 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 4 hours. The reaction mixture was neutralised with 1M citric acid and diluted with water and EtOAc. The organic layer was separated and the aqueous layer re-extracted with EtOAc. The combined organics were washed with saturated brine, dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0 to 50% EtOAc in isohexane to afford the product (251 mg, 35.1%). m/z (ES+) (M+H)+=723.67; HPLC tR=3.75 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[C:13]([CH3:37])=[C:14]([N:18]([CH2:22][C:23]2[CH:35]=[CH:34][C:26]([O:27][CH2:28][C:29]([O:31]CC)=[O:30])=[C:25]([CH3:36])[CH:24]=2)[CH2:19][CH2:20][CH3:21])[CH:15]=[CH:16][CH:17]=1>>[CH3:37][C:13]1[C:14]([N:18]([CH2:22][C:23]2[CH:35]=[CH:34][C:26]([O:27][CH2:28][C:29]([OH:31])=[O:30])=[C:25]([CH3:36])[CH:24]=2)[CH2:19][CH2:20][CH3:21])=[CH:15][CH:16]=[CH:17][C:12]=1[C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(Br)c1C
Product: CCCN(Cc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(C)cc2)c1C

Procedure:
Prepared from 4-methylphenylboronic acid and ethyl (4-{[(3-bromo-2-methylphenyl)(propyl)amino]methyl}-2-methylphenoxy)acetate using the procedure described for Example 25 (Method A).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][C@@H:5]([C:8]([OH:10])=O)[CH2:4][CH:3]=1.C1(C)C=CC=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(Cl)(=O)C([Cl:29])=O>ClCCl.CN(C)C=O>[CH3:1][C:2]1[CH2:7][CH2:6][C@@H:5]([C:8]([Cl:29])=[O:10])[CH2:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1=CC[C@H](C(=O)O)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC1=CC[C@H](C(=O)Cl)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(R)-4-methylcyclohex-3-enecarboxylic acid 503 (371 mg, 2.65 mmol), azeotropically dried by evaporation from toluene, was treated with potassium phosphate tribasic (1.13 g, 7.94 mmol), suspended in dichloromethane (7.6 mL) and treated with dimethylformamide (4 drops). The reaction mixture was cooled to 0° C. and treated dropwise with oxalyl chloride (0.75 mL, 7.9 mmol). The reaction mixture was allowed to warm to ambient temperature while stirring for 2 hours. After filtering the solids, the solution was concentrated, treated with hexanes and concentrated again to afford (R)-4-methylcyclohex-3-enecarbonyl chloride 504 as a light yellow oil which was used immediately in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[C:4]([CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][C:7]1=[O:13])=[O:5].[N+](=[CH2:21])=[N-].CC1C=CC(S(N(N=O)C)(=O)=O)=CC=1>CCOCC>[CH3:21][O:12][C:11]1[CH2:10][CH2:9][CH2:8][C:7](=[O:13])[C:6]=1[C:4](=[O:5])[C:3]1[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:2]=1[Cl:1]
Reactant: O=C1CCCC(=O)C1C(=O)c1ccc(Cl)cc1Cl
Reactant: C=[N+]=[N-]
Agent: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Solvent: CCOCC
Product: COC1=C(C(=O)c2ccc(Cl)cc2Cl)C(=O)CCC1
Yield: 35 %

Procedure:
2-(2,4-Dichlorobenzoyl)cyclohexane-1,3-dione (2.85 g, 0.01 ml) was stirred as a suspension in 25 ml anhydrous ether. Diazomethane, generated from Diazald™ (50 ml, 0.02 mol) was added at 0° at a rate slow enough to control effervescence. The resulting solution was stirred for an hour and the solvent allowed to evaporated under a stream of nitrogen in a beaker. The resulting oil was dissolved in ether and washed twice with saturated aqueous K2CO3. Evaporation of the solvent under reduced pressure yielded a solid (1.0 g, 35%, m.p. 81°-86° C.), the nuclear magnetic, infrared and mass spectra of which were consistent with the structure.
Reaction SMILES: [CH:1]([C:3]1[C:12]([CH3:13])=[C:11]([CH3:14])[C:10]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:26]=[CH:25][N:24]([CH3:27])[N:23]=3)=[CH:18][CH:17]=2)=[CH:9][C:4]=1[C:5](OC)=[O:6])=O.Cl.[NH2:29][C@H:30]1[CH2:34][CH2:33][CH2:32][C@@H:31]1[OH:35].C(N(CC)CC)C.S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1>[OH:35][C@H:31]1[CH2:32][CH2:33][CH2:34][C@@H:30]1[N:29]1[CH2:1][C:3]2[C:4](=[CH:9][C:10]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:26]=[CH:25][N:24]([CH3:27])[N:23]=4)=[CH:18][CH:17]=3)=[C:11]([CH3:14])[C:12]=2[CH3:13])[C:5]1=[O:6]
Reactant: N[C@H]1CCC[C@@H]1O
Reactant: COC(=O)c1cc(Cc2ccc(-c3ccn(C)n3)cc2)c(C)c(C)c1C=O
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(Cc2ccc(-c3ccn(C)n3)cc2)cc2c(c1C)CN([C@H]1CCC[C@@H]1O)C2=O
Temperature: 25 °C
Reaction time: 7.5 h
Yield: 44.2 %

Procedure:
A solution of methyl 2-formyl-3,4-dimethyl-5-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)benzoate (0.09 g), (1S,2S)-2-aminocyclopentanol hydrochloride (0.03 g), triethylamine (0.03 mL) and anhydrous magnesium sulfate (0.06 g) in THF (1.80 mL) was stirred at room temperature for 46 hr under nitrogen atmosphere. The insoluble substance was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was diluted with methanol (1.80 mL) and THF (1.80 mL), sodium triacetoxyborohydride (0.10 g) was added thereto, and the mixture was stirred at room temperature for 7.5 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.04 g).
Reaction SMILES: C(O[C:6](=[O:26])[NH:7][C@@H:8]([CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C@@H:9]([OH:13])[C:10]#[C:11][CH3:12])(C)(C)C.C(O)(C(F)(F)F)=O.C(N(CC)C(C)C)(C)C.C1C=CC2N(O)N=NC=2C=1.[C:53]([NH:60][C@H:61](C(O)=O)[CH2:62][CH2:63][S:64][CH3:65])([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH2:19]([O:18][C:16](=[O:17])[NH:15][CH2:14][C@H:8]([NH:7][C:6](=[O:26])[C@@H:61]([NH:60][C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:62][CH2:63][S:64][CH3:65])[C@@H:9]([OH:13])[C:10]#[C:11][CH3:12])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC#C[C@H](O)[C@H](CNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC#C[C@H](O)[C@H](CNC(=O)OCc1ccccc1)NC(=O)[C@H](CCSC)NC(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 78.2 %

Procedure:
A solution of [1S,2S]-[1-(benzyloxycarbonylamino-methyl)-2-hydroxy-pent-3-ynyl]-carbamic acid tert-butyl ester (1.19 g, 3.29 mmol, prepared as described in WO PCT 0250019) was dissolved in CH2Cl2 (20 mL) and treated with TFA (10 mL). The solution was stirred for 3 h and then concentrated in vacuo. The residue was dissolved in CH2Cl2 and concentrated in vacuo; this procedure was repeated. The residue was dissolved in CH2Cl2 (30 mL). The resultant solution was charged sequentially with N, N-diisopropylethylamine (2.3 mL, 13.2 mmol), HOBt (466 mg, 3.45 mmol), N-Boc methionine (820 mg, 3.29 mmol), and BOP (1.53 g, 3.45 mmol). The reaction was stirred for 12 h and partitioned between EtOAc and sat. NH4Cl. The organic phase was washed with sat. NaHCO3 and brine, and then dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford [2S,3S]-[2-[(2S)-(2-tert-butoxycarbonylamino-4-methylsulfanyl-butyrylamino)]-3-hydroxy-hex-4-ynyl]-carbamic acid benzyl ester (1.27 g, 78% yield). MS found: (M+Na)+=516.3.
Reaction SMILES: [F:1][C:2]1[C:3]([Cl:12])=[C:4](Br)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[CH3:13][C@@H:14]1[CH2:19][NH:18][CH2:17][CH2:16][NH:15]1>>[ClH:12].[F:1][C:2]1[C:3]([Cl:12])=[C:4]([N:18]2[CH2:17][CH2:16][NH:15][C@H:14]([CH3:13])[CH2:19]2)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1
Reactant: Fc1cc2ccoc2c(Br)c1Cl
Reactant: C[C@@H]1CNCCN1
Product: C[C@@H]1CN(c2c(Cl)c(F)cc3ccoc23)CCN1
Product: Cl

Procedure:
Beginning with 0.24 gm (0.95 mmol) 5-fluoro-6-chloro-7-bromobenzofuran and 0.09 gm (0.95 mmol) 2(R)-methylpiperazine, the title compound was prepared essentially as described in GENERAL PROCEDURE IV.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:4][CH:5]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([C:27]([F:30])([F:29])[F:28])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[C:7](=[O:9])[CH:8]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[O:9]=[C:7]1[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([C:27]([F:30])([F:29])[F:28])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)=[CH:5][O:4][C:3]([CH2:2][O:1][S:39]([CH3:38])(=[O:41])=[O:40])=[CH:8]1
Reactant: CS(=O)(=O)Cl
Reactant: O=c1cc(CO)occ1OCCCCCSc1ccnc2cc(C(F)(F)F)ccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1cc(=O)c(OCCCCCSc2ccnc3cc(C(F)(F)F)ccc23)co1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 2-hydroxymethyl-5-[5-(7-trifluoromethyl-quinolin-4-ylsulfanyl)-pentyloxy]-4H-pyran-4-one EHT 5909 (0.10 g, 0.23 mmol) in 4 mL of dichloromethane at 5° C. were added triethylamine (35 μl, 0.25 mmol) and methanesulfonyl chloride (19.4 μl, 0.25 mmol). The reaction mixture was stirred 18 h at room temperature. Dichloromethane (20 mL) was added and the solution was washed with aqueous NaHCO3 10% (2×30 mL). The organic layer was dried over MgSO4, filtered and evaporated in vacuo. The crude product was purified by chromatography on silica using as eluent CH2Cl2:MeOH=98:2. After evaporation methanesulfonic acid 4-oxo-5-[6-(7-trifluoromethyl-quinolin-4-ylsulfanyl)-hexyloxy]-4H-pyran-2-ylmethyl ester 9 (83 mg, 69%) was obtained as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[C:21]([C:24]1[CH:29]=[C:28]([Cl:30])[C:27]([NH:31][C:32](=[O:43])[CH2:33][N:34]2[CH2:39][CH2:38][NH:37][CH:36]([C:40]([NH2:42])=[O:41])[CH2:35]2)=[C:26]([Cl:44])[CH:25]=1)(=[O:23])[CH3:22].C(N(CC)CC)C>CN(C)C=O>[ClH:30].[ClH:30].[C:21]([C:24]1[CH:29]=[C:28]([Cl:30])[C:27]([NH:31][C:32](=[O:43])[CH2:33][N:34]2[CH2:39][CH2:38][N:37]([CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[C:7]3[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=3)[CH:36]([C:40]([NH2:42])=[O:41])[CH2:35]2)=[C:26]([Cl:44])[CH:25]=1)(=[O:23])[CH3:22]
Reactant: Fc1ccc(C(CCCCBr)c2ccc(F)cc2)cc1
Reactant: CC(=O)c1cc(Cl)c(NC(=O)CN2CCNC(C(N)=O)C2)c(Cl)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)c1cc(Cl)c(NC(=O)CN2CCN(CCCCC(c3ccc(F)cc3)c3ccc(F)cc3)C(C(N)=O)C2)c(Cl)c1
Product: Cl
Temperature: 70 °C
Yield: 24 %

Procedure:
A mixture of 5.9 parts of 1,1'-(5-bromo-1-pentylidene)bis[4-fluorobenzene], 5.6 parts of N-(4-acetyl-2,6-dichlorophenyl)-3-(aminocarbonyl)-1-piperazineacetamide, 4.05 parts of N,N-diethylethanamine and 90 parts of N,N-dimethylformamide was stirred over weekend at 70° C. After evaporation, the residue was taken up in dichloromethane. The organic layer was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in acetonitrile and 2-propanol. The salt was filtered off and dried, yielding 2.54 parts (24.0%) of N-(4-acetyl-2,6-dichlorophenyl)-3-(aminocarbonyl)-4-[5,5-bis(4-fluorophenyl)pentyl]-1-piperazineacetamide dihydrochloride; mp. 181.2° C. (compound 14).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16]([C:18]1[CH:38]=[CH:37][C:21]([C:22]([NH:24][C@H:25]([C:27]2[NH:31][C:30]3[CH:32]=[CH:33][C:34]([Cl:36])=[CH:35][C:29]=3[N:28]=2)[CH3:26])=[O:23])=[CH:20][C:19]=1[Cl:39])=[O:17])=O)(C)(C)C.FC(F)(F)C(O)=O.ClCCl.CO.N.ClCl>>[NH2:8][CH2:9][CH2:10][C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16]([C:18]1[CH:38]=[CH:37][C:21]([C:22]([NH:24][C@H:25]([C:27]2[NH:31][C:30]3[CH:32]=[CH:33][C:34]([Cl:36])=[CH:35][C:29]=3[N:28]=2)[CH3:26])=[O:23])=[CH:20][C:19]=1[Cl:39])=[O:17]
Reactant: C[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@@H]2CCNC(=O)OC(C)(C)C)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Agent: N
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@@H]2CCN)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 17 from 4-[(2R)-2-(tert-butoxycarbonylamino)ethylpyrrolidin-1-ylcarbonyl]-3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethyl]benzamide and trifluoroacetic acid. Yield: quantitative; Rf value: 0.18 (silica gel; dichloromethane/methanol/ammonia=9:1:0.1); C23H25Cl2N5O2 (474.39); mass spectrum: (M+H)+=474/476 (chlorine isotope) and (M−H)−=472/474 (chlorine isotope).